Abstract
Metformin may exert anticancer effects through indirect (mediated by metabolic changes) or direct mechanisms. The goal was to examine metformin impact on metabolic factors in non-diabetic subjects and determine whether this impact varies by baseline BMI, insulin, and rs11212617 SNP in CCTG MA.32, a double-blind placebo-controlled randomized adjuvant breast cancer (BC) trial. 3649 subjects with T1-3, N0-3, M0 BC were randomized; pretreatment and 6-month on-treatment fasting plasma was centrally assayed for insulin, leptin, highly sensitive C-reactive protein (hsCRP). Glucose was measured locally and homeostasis model assessment (HOMA) calculated. Genomic DNA was analyzed for the rs11212617 SNP. Absolute and relative change of metabolic factors (metformin versus placebo) were compared using Wilcoxon rank and t-tests. Regression models were adjusted for baseline differences and assessed interactions with baseline BMI, insulin, and the SNP. Mean age was 52 years. The majority had T2/3, node positive, hormone receptor positive, HER2 negative BC treated with (neo)adjuvant chemotherapy and hormone therapy. Median baseline body mass index (BMI) was 27.4 kg/m2 (metformin) and 27.3 kg/m2 (placebo). Median weight change was −1.4 kg (metformin) vs +0.5 kg (placebo). Significant improvements were seen in all metabolic factors, with 6 month standardized ratios (metformin/placebo) of 0.85 (insulin), 0.83 (HOMA), 0.80 (leptin), and 0.84 (hsCRP), with no qualitative interactions with baseline BMI or insulin. Changes did not differ by rs11212617 allele. Metformin (vs placebo) led to significant improvements in weight and metabolic factors; these changes did not differ by rs11212617 allele status.
Highlights
The anti-diabetes drug metformin has been associated with reduced cancer risk and improved cancer prognosis in observational studies[1,2]; it may exert beneficial effects on cancer through both indirect and direct mechanisms
These improvements with metformin were independent of baseline body mass index (BMI) and insulin levels and did not vary by rs11212617 genotype
The borderline significant interactions of baseline BMI with change in leptin and of insulin with change in highly sensitive C-reactive protein (hsCRP) may have been due to chance they warrant evaluation in future studies; it is important to note that these potential interactions were quantitative, not qualitative with metformin benefits being consistently observed
Summary
The anti-diabetes drug metformin has been associated with reduced cancer risk and improved cancer prognosis in observational studies[1,2]; it may exert beneficial effects on cancer through both indirect and direct mechanisms. Indirect effects are likely mediated by systemic reductions in insulin, which results in decreased tumor-specific activation of the insulin receptor (IR) and suppression of mitogenic PI3K and Ras signaling[3]. Metformin may exhibit direct inhibitory effects on cancer cells that are achieved by liver kinase B1 (LKB1)-mediated activation of AMPactivated protein kinase (AMPK), a negative regulator of PI3K/Akt/ mTOR signaling and protein synthesis[4]. Canadian Cancer Trials Group (CCTG) MA.[32] was initiated in 2010 to test the effect of metformin (versus placebo) on breast cancer (BC) outcomes in women with high-risk early-stage BC cancer who were receiving standard therapy.
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